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Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

Jonathan P Gumucio, Austin H Qasawa, Patrick J Ferrara, Afshan N Malik, Katsuhiko Funai, Brian McDonagh, Christopher L Mendias

Preprint posted on November 18, 2018 https://www.biorxiv.org/content/early/2018/11/18/471979

Why do lipids accumulate following muscle injury? A multi-omics study points to mitochondrial and lipid metabolism dysfunction.

Selected by Pablo Ranea Robles

Introduction

Do you know anyone that had a muscle injury while heavy lifting or practicing sports? Sure you do. Chronic muscle injuries provoke the loss of mobility in the patients, imposing a burden on health care and workers’ compensation systems. Among the muscles usually prone to injury, the rotator cuff is one of the most affected. The rotator cuff is a group of muscles and tendons that stabilize the shoulder joint and let us lift and rotate our arms (Figure 1).

Rotator cuff anatomy

Figure 1. The anatomy of the human rotator cuff. Credit: Harvard Health Publishing

 

Have you ever wondered what changes happen in that injured muscle after the injury? One of the best characterized effects of muscle injury is pathological lipid accumulation. This is known as myosteatosis (from the Greek words myos-, muscle, steatos-, fat, and -osis, formation). The rotator cuff is particularly susceptible to develop pathological lipid accumulation after injury.  Importantly, lipid accumulation in this muscle after injury correlates with a poor outcome after surgical repair (Gladstone et al., 2007). Moreover, recurrence of tears after the injury is quite common in this type of injuries (Isaac et al., 2012). It is known that lipid excess likely impairs muscle regeneration, but the mechanisms driving lipid accumulation in myosteatosis remain largely unknown.

In this study, Gumucio and coworkers used a rat model of rotator cuff injury (Gumucio et al., 2018). The anatomy of the rotator cuff in rats is similar to humans, and this model mimics many of the pathological changes observed in patients with chronic rotator cuff tears (Soslowsky et al., 1996). They studied the supraspinatus muscle, one of the muscles of the rotator cuff (supraspinatus, infraspinatus, teres minor, and subscapularis). Experimental groups were uninjured and injured rats, either 10, 30, or 60 days after the injury. They aimed to characterize the biochemical and cellular pathways that lead to myosteatosis after skeletal muscle injury.

Key findings

They characterized the changes in muscle fiber force production and the biological changes after injury by the integration of different -omics techniques. They evaluated alterations in the rotator cuff transcriptome (by RNA sequencing), proteome, metabolome, and lipidome (using mass spectrometry). The main outcome was the identification of mitochondrial dysfunction and impaired fatty acid oxidation as strong drivers of the pathological steatosis after muscle injury. Then, they studied in detail the hypothesis that mitochondrial dysfunction drives pathological lipid accumulation in torn rotator cuff muscles.

Shotgun lipidomics revealed expected increases in different lipid species at different time points in the injured muscles, such as free fatty acids (FFA), triglycerides, ceramides, sphingomyelins, and some phospholipids. Other lipids displayed a biphasic response, like cholesterol esters, diacylglycerides, and other phospholipids.

The metabolomics data revealed a decrease in nucleoside and nucleotide metabolites, concomitant with an increase in glycolytic and pentose phosphate pathway metabolites. The transcriptomics data showed an induction of well-known pathways in muscle injury, such as autophagy, atrophy, inflammation or fibrosis. It is worth to highlight the decreased mRNA expression of genes involved in mitochondrial function (Krebs cycle and OXPHOS system), lipid uptake and metabolism, and fatty acid oxidation, which was confirmed by proteomics data. Another aspect that appeared in the transcriptomics and proteomics data is oxidative stress. This is deduced due to the increase reactive oxygen species (ROS)-related genes and proteins amount. Moreover, omega-oxidation and peroxisomal metabolism were induced, since transcriptomics data showed augmented expression of Acox1 (Acyl-CoA oxidase 1, an enzyme of peroxisomal beta-oxidation) and Cyp4b1 (from the cytochrome P450 family, related to omega-oxidation of fatty acids). These pathways are usually active when mitochondrial fatty acid oxidation is impaired. These data, together with the increased glycolytic metabolites point to a metabolic shift in injured muscles, from fatty acid oxidation and oxidative phosphorylation to glycolysis.

Finally, a deeper study on mitochondrial function demonstrated that mitochondrial metabolism is impaired in injured muscles, as shown by a reduction in the activity of complexes I, II, and IV, an increase of some antioxidant proteins, and a reduction in the oxidation rate of pyruvate and palmitate. However, mitochondrial content seems to be equal in injured and non-injured muscles, since mitochondrial DNA levels were similar in both groups.

Future directions and questions for authors

Some aspects of this study deserve more attention. For instance, what is the shape of mitochondria in injured muscles? Are they smaller or bigger? Is there peroxisomal proliferation in injured muscles, given the increase of peroxisomal metabolism? Which are the species of acylcarnitines measured? If fatty acid oxidation is impaired, one would expect an increase in some of the acylcarnitines species. Is there autophagy impairment in the injured muscles? The p62 accumulation observed in injured muscles is a classical marker of autophagy impairment. After this study, it would be of interest to know which the next steps are. Can these altered pathways be modulated by drugs? In this way, we would be able to study their effect on muscle regeneration after injury. It would be also of interest to compare human samples from injured muscles with non-injured muscles, to see if these changes are conserved. Finally, one important weakness of this study is that it has been performed only in male rats. Fat content and metabolism is different between men and women, so more studies in female individuals of animal models need to be done to fully understand the pathophysiology of muscle injuries.

What I liked about the study

I liked that the authors integrated different -omics data to gain insights into the molecular physiology of muscle injury. This kind of unbiased approach can shed light on hidden pathological mechanisms. Here, they uncovered a central role of mitochondrial and lipid metabolism in the development of myosteatosis after muscle injury.

 

References:

Gladstone, J. N., Bishop, J. Y., Lo, I. K. Y. and Flatow, E. L. (2007). Fatty Infiltration and Atrophy of the Rotator Cuff do not Improve after Rotator Cuff Repair and Correlate with Poor Functional Outcome. Am. J. Sports Med. 35, 719–728.

Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B. and Mendias, C. L. (2018). Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. bioRxiv 471979.

Isaac, C., Gharaibeh, B., Witt, M., Wright, V. J. and Huard, J. (2012). Biologic approaches to enhance rotator cuff healing after injury. J. shoulder Elb. Surg. 21, 181–90.

Soslowsky, L. J., Carpenter, J. E., DeBano, C. M., Banerji, I. and Moalli, M. R. (1996). Development and use of an animal model for investigations on rotator cuff disease. J. shoulder Elb. Surg. 5, 383–92.

Tags: lesion, muscular, rehabilitation

Posted on: 7th January 2019

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